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Suppression of erythropoiesis by dietary nitrate

Suppression of erythropoiesis by dietary nitrate
Suppression of erythropoiesis by dietary nitrate
In mammals, hypoxia-triggered erythropoietin release increases red blood cell mass to meet tissue oxygen demands. Using male Wistar rats, we unmask a previously unrecognized regulatory pathway of erythropoiesis involving suppressor control by the NO metabolite and ubiquitous dietary component nitrate. We find that circulating hemoglobin levels are modulated by nitrate at concentrations achievable by dietary intervention under normoxic and hypoxic conditions; a moderate dose of nitrate administered via the drinking water (7 mg NaNO3/kg body weight/d) lowered hemoglobin concentration and hematocrit after 6 d compared with nonsupplemented/NaCl-supplemented controls. The underlying mechanism is suppression of hepatic erythropoietin expression associated with the downregulation of tissue hypoxia markers, suggesting increased pO2. At higher nitrate doses, however, a partial reversal of this effect occurred; this was accompanied by increased renal erythropoietin expression and stabilization of hypoxia-inducible factors, likely brought about by the relative anemia. Thus, hepatic and renal hypoxia-sensing pathways act in concert to modulate hemoglobin in response to nitrate, converging at an optimal minimal hemoglobin concentration appropriate to the environmental/physiologic situation. Suppression of hepatic erythropoietin expression by nitrate may thus act to decrease blood viscosity while matching oxygen supply to demand, whereas renal oxygen sensing could act as a brake, averting a potentially detrimental fall in hematocrit.—Ashmore, T., Fernandez, B. O., Evans, C. E., Huang, Y., Branco-Price, C., Griffin, J. L., Johnson, R. S., Feelisch, M., and Murray, A. J. Suppression of erythropoiesis by dietary nitrate.
kidney, oxygen sensing, hypoxia
0892-6638
1102-1112
Ashmore, Tom
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Fernandez, B.O.
9890aabc-1fe6-4530-a51e-31182e537131
Evans, Colin E.
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Huang, Yun
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Branco-Price, Cristina
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Griffin, Julian L.
efbf2925-ee1c-4e28-8e89-c1a70d143928
Johnson, Randall S.
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Feelisch, Martin
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Murray, Andrew J.
cec08ce8-91ec-42c6-9746-c4a0d9306e7b
Ashmore, Tom
3c15ded2-cdd0-4ca1-966e-39dd8dd7f80d
Fernandez, B.O.
9890aabc-1fe6-4530-a51e-31182e537131
Evans, Colin E.
24023ffb-c0fc-450b-81d1-9e27ef250668
Huang, Yun
b2d70c2c-e0d5-4fa9-846a-6d71df29cce4
Branco-Price, Cristina
61b8fa9a-c39c-4e2c-8e4d-fe4f54d8423e
Griffin, Julian L.
efbf2925-ee1c-4e28-8e89-c1a70d143928
Johnson, Randall S.
f76ee722-08df-4010-b5c9-684689e9872c
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Murray, Andrew J.
cec08ce8-91ec-42c6-9746-c4a0d9306e7b

Ashmore, Tom, Fernandez, B.O., Evans, Colin E., Huang, Yun, Branco-Price, Cristina, Griffin, Julian L., Johnson, Randall S., Feelisch, Martin and Murray, Andrew J. (2014) Suppression of erythropoiesis by dietary nitrate. The FASEB Journal, 29 (3), 1102-1112. (doi:10.1096/fj.14-263004).

Record type: Article

Abstract

In mammals, hypoxia-triggered erythropoietin release increases red blood cell mass to meet tissue oxygen demands. Using male Wistar rats, we unmask a previously unrecognized regulatory pathway of erythropoiesis involving suppressor control by the NO metabolite and ubiquitous dietary component nitrate. We find that circulating hemoglobin levels are modulated by nitrate at concentrations achievable by dietary intervention under normoxic and hypoxic conditions; a moderate dose of nitrate administered via the drinking water (7 mg NaNO3/kg body weight/d) lowered hemoglobin concentration and hematocrit after 6 d compared with nonsupplemented/NaCl-supplemented controls. The underlying mechanism is suppression of hepatic erythropoietin expression associated with the downregulation of tissue hypoxia markers, suggesting increased pO2. At higher nitrate doses, however, a partial reversal of this effect occurred; this was accompanied by increased renal erythropoietin expression and stabilization of hypoxia-inducible factors, likely brought about by the relative anemia. Thus, hepatic and renal hypoxia-sensing pathways act in concert to modulate hemoglobin in response to nitrate, converging at an optimal minimal hemoglobin concentration appropriate to the environmental/physiologic situation. Suppression of hepatic erythropoietin expression by nitrate may thus act to decrease blood viscosity while matching oxygen supply to demand, whereas renal oxygen sensing could act as a brake, averting a potentially detrimental fall in hematocrit.—Ashmore, T., Fernandez, B. O., Evans, C. E., Huang, Y., Branco-Price, C., Griffin, J. L., Johnson, R. S., Feelisch, M., and Murray, A. J. Suppression of erythropoiesis by dietary nitrate.

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Published date: 24 November 2014
Keywords: kidney, oxygen sensing, hypoxia
Organisations: Faculty of Medicine

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Local EPrints ID: 372110
URI: http://eprints.soton.ac.uk/id/eprint/372110
ISSN: 0892-6638
PURE UUID: e212488b-3c87-487b-be59-40d6fb5efdc0
ORCID for B.O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 25 Nov 2014 11:43
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Tom Ashmore
Author: B.O. Fernandez ORCID iD
Author: Colin E. Evans
Author: Yun Huang
Author: Cristina Branco-Price
Author: Julian L. Griffin
Author: Randall S. Johnson
Author: Martin Feelisch ORCID iD
Author: Andrew J. Murray

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